Allelic Variation in CYP3A4 and PLB1 Drives Feed Efficiency and Immunometabolic Resilience in Beef Cattle

We evaluated genetic markers for feed efficiency and immunocompetence in 108 crossbred steers (217 ± 8.2 kg) fed a high-forage total mixed ration for 35 days, using GrowSafe8000 intake nodes to calculate residual feed intake (RFI). From the 20 most efficient (low-RFI) and 20 least efficient (high-RFI) animals, we genotyped three metabolic loci (CYP3A4 rs438103222, PLB1 rs456635825, CRAT rs876019788) and profiled blood mRNA levels of these plus eight innate/adaptive immune genes. Logistic regression revealed that CYP3A4 and PLB1 polymorphisms—but not CRAT—were strongly associated with initial and final body weight, average daily gain, and feed intake: CYP3A4 A/A and PLB1 A-allele carriers achieved superior growth on reduced feed. Haplotype reconstruction across the three loci defined eight multi-SNP combinations, with the C-A-A haplotype enriched in low-RFI steers and combinations harboring CYP3A4 A and PLB1 A alleles linked to low RFI. Intriguingly, these favorable genotypes also overlapped with up-regulation of immune sensors and effectors (e.g., CD14, TLR4, TNF-α), indicating a coordinated metabolic–immune adaptation in efficient cattle. Collectively, our results validate CYP3A4 and PLB1 as high-impact quantitative trait nucleotides for marker-assisted selection aimed at simultaneously improving feed efficiency and immune resilience in beef production.